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Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC. [ABSTRACT FROM AUTHOR]

Highly efficient persulfate oxidation process activated with pre-magnetization Fe0 (pre-magnetization Fe0/PS) was employed to degrade Orange anthraquinone dye at different Fe0 dosages (1-8 mmol/L), initial pH levels (3-10) and PS dosages (2-8 mmol/L). Pre-magnetization Fe0/PS possessed 8.4-119.6 folds enhancement in degradation rate and could widen pH range and save 90% Fe0 and PS dosage when compared with conventional Fe0/PS process. And this effect was ascribed to the change of Fe0 characteristics after pre-magnetization. This significant improvement was also observed on the degradation of many refractory contaminants of tartrazine, phenol, 2,4-dichlorophenol (2,4-DCP), p-chlorophenol, chlorobenzene, nitrobenzene, p-nitrophenol and p-nitrchlorobenzene, which were 2.8-11.4 folds of those by Fe0/PS process. Pre-magnetization Fe0/PS is a more promising process since it does not require any change of the present water and wastewater treatment process, and does not need an extra energy source, costly materials, and complex equipment. [ABSTRACT FROM AUTHOR]

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention. [ABSTRACT FROM AUTHOR]

Osmotic pressure provided by salty wastewaters is an important influencing factor for alginate-like exopolysaccharides (ALE) in aerobic granular sludge (AGS). Therefore, research on the influence of salinity (NaCl 0 R1, 10 g/L R2, 30 g/L R3) on AGS and its ALE formation was conducted. A salinity of 1% induced larger particle size with smooth spheroidal shape and enhanced granular strength in R2. The TOC and ammonia removal were unaffected in both R2 and R3, but the P removal was greatly enhanced. ALE was much enriched at moderate salinity (1% NaCl). The amount of ALE reached 49.8 mg/g VSS at 140 d in R2, which was much higher than in R1 (26.8 mg/g VSS) and R3 (28.9 mg/g VSS), possibly due to the activation of gene algC expression in AGS of R2. ALE also showed the largest GG block fractionation and MW in R2, which indicated the greatest enhancement of mechanical properties. Moreover, enrichment of glucosamine, lipid content, and octadecanamide derivative in ALE of R2 endowed it with medicinal potential, stronger water-barrier property, and reduction of the products' friction coefficients, respectively. Therefore, AGS based on ALE is a potential technology for treatment of salty wastewater. [ABSTRACT FROM AUTHOR]

Objective: Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Poor prognosis and low survival rates have driven the development of novel therapeutic strategies. Nanosecond pulsed electric field has emerged as a novel, minimal invasive and non-thermal treatment for solid tumors. It is of great significance to study the combination therapy of nsPEF and other treatment strategies for pancreatic cancer. Methods: We developed neutrophil membrane-wrapped liposomal nanoparticles loaded with gemcitabine (NE/Lip-GEM) and investigated their use as a complementary agent for nsPEF treatment. Results: Our results showed that neutrophil-mediated delivery of liposomal-gemcitabine (NE/Lip-GEM) efficiently inhibited the growth of pancreatic tumors in mice whose has been treated with incomplete nsPEF ablation. Conclusions: The combination of nsPEF and NE/Lip-GEM may be a promising synergistic strategy for pancreatic cancer therapy [ABSTRACT FROM AUTHOR]